Leishmania species have emerged as excellent model systems for the study of molecular genetics of infectious diseases, in addition to their importance as human pathogens. I am going to employ the genetic approach of functional complementation to study the virulence properties of Leishmania. The success of this strategy has been demonstrated by the complementation of several mutant lines of L. donovani lacking lipophosphoglycan (LPG) a cell-surface virulence determinant. I plan to use this method to select for restoration of virulence properties other than LPG expression. I will infect BALB/c mice with a pool of avirulent L. major parasites that have been transfected with a cosmid library from a virulent strain of the parasite. Only those parasites with restored virulence will be allowed to resist the mouse's defense and form a lesion, from which they can be recovered for genetic and molecular analysis. Using this approach, l will pursue gene(s) responsible for enhanced virulence. I will also analyze the function and the expression of the gene(s) in the life cycle of the parasite and at different stages of the infection. My attention will also be focused on learning novel biochemical and molecular pathways and/or regulatory mechanisms that are unique for this parasite and could lead to new strategies for chemotherapeutic attack of this disease.